Study found 31% of EBV ME/CFS patients achieved full remission on spironolactone 25 mg daily

Hip

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A 2020 study gave spironolactone 25 mg daily to sixteen Epstein-Barr virus ME/CFS patients, and found that 31% achieved full remission from their illness, and the other 69% observed improvements in their ME/CFS symptoms.

Spironolactone is a diuretic drug, which is also prescribed for high blood pressure and edema (fluid retention).



One 2016 study found that spironolactone has antiviral effects against EBV in vitro, by inhibiting EBV SM protein function. However, according to a calculation in this post, blood concentrations of spironolactone are too low to achieve the same antiviral effect in vivo, when you take this drug.

So the benefit of spironolactone for EBV ME/CFS may come from some other actions that this drug has in the body. One possibility is spironolactone's potential anti-inflammatory effects:

Spironolactone has potent anti-mineralocorticoid effects (it blocks the action of aldosterone by blocking the mineralocorticoid receptor). Ref: here.

This may thus make spironolactone anti-inflammatory, as "aldosterone promotes an inflammatory state characterized by vascular infiltration of immune cells, reactive oxidative stress, and proinflammatory cytokine production". Ref: here.



Spironolactone is generally a well-tolerated drug. Note that spironolactone lowers blood volume as well as blood pressure, and lowers testosterone levels. Spironolactone increases blood potassium levels, so potassium supplements are contraindicated when taking spironolactone. Spironolactone can cause gynecomastia in males if taken for long periods (eg a year).
 

Alvin2

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What an interesting study.
And while i would not want to take this long term a positive result to it would likely give huge direction as to the cause of one's symptoms if they respond to it.
And best part is that its a generic drug, no thousands of dollars a month to buy it (if you can get it prescribed).
 

nyanko_the_sane

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I would have liked some of this drug back in 2004, oh well....

Epstein–Barr virus (Wikipedia)
Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity.
 
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Art Vandelay

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A 2020 study gave spironolactone 25 mg daily to sixteen Epstein-Barr virus ME/CFS patients, and found that 31% achieved full remission from their illness, and the other 69% observed improvements in their ME/CFS symptoms.
This is an extremely poor quality study (if it can be called that as I believe it was just a poster for a conference).

There's no control group, no blinding, subjective outcome criteria and it doesn't even specify what diagnostic criteria were used. It also doesn't specify how 'remission' was defined.

This just demonstrates that most doctors have no idea on how to run proper clinical trials.

For what it's worth, I was prescribed spironolactone in the late 90s as a friend who was a doctor was a colleague of an endocrinologist who was experimenting with it with his ME/CFS patients. It did nothing for me. (I had an EBV onset.)


ETA: a number of people in a local support group have seen the first author who is a specialist at a Qld hospital and have been put on spironolactone. I imagine they would have reported any miraculous recoveries if they had occurred. The second author is apparently consulting at a 'regenerative' clinic.
 
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It lowers blood volume? You think that would be bad for every single ME patient, weird it helped some. But then again all these treatments appear to be different.

For example I tried Nimodipine several times and even at tiny doses I had some unpleasant side effects, primarily being awake all night, muscle pain and a very bad sore throat. For all I know it was helping, but the insomnia and other side effects weren't worthit.

Also so many of these drugs have bad effects on men vs women, testicular toxicity, lowering t levels, or other t based effects. E.g. Tagamet for ebv.

This seems like another possible contender, but if it's effect is purely anti inflammatory then andrographolide is probably just as potent.

One study:
5. Conclusions
Andrographolide has anti-inflammatory effect and significantly inhibits the expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 cells. Its anti-inflammatory mechanism may be through the inhibition of NF-κB and MAPKs signaling pathway.
Would be interesting to know if Spironolactone effects the same cytokines.
 

pattismith

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it's difficult to judge the interest of the study based on this abstract...

how long have been ill the patients before starting the trial?
what criteria did they use for EBV positive serology (IgG? IgM?...)
How long was the spironolactone trial?
And for those who responded , what were the datas?
etc

On the other hand, it's a rather safe drug, so maybe worth a trial
 

Hipsman

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Awesome, Hip! added to my to try list even thou I most likely don't have EBV. This drug is very cheap 2$ for month worth of supply in local pharmacy, how long do you think it takes for it to start working?
 

pattismith

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It lowers blood volume? You think that would be bad for every single ME patient, weird it helped some. But then again all these treatments appear to be different.

For example I tried Nimodipine several times and even at tiny doses I had some unpleasant side effects, primarily being awake all night, muscle pain and a very bad sore throat. For all I know it was helping, but the insomnia and other side effects weren't worthit.

Also so many of these drugs have bad effects on men vs women, testicular toxicity, lowering t levels, or other t based effects. E.g. Tagamet for ebv.

This seems like another possible contender, but if it's effect is purely anti inflammatory then andrographolide is probably just as potent.

One study:


Would be interesting to know if Spironolactone effects the same cytokines.
:thumbsup:

Andrographolide has anti TLR activity, and it has shown anti-psoriatic effect, like Sinapis Alba (mustard)

Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation | Phoenix Rising ME/CFS Forums
 
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This is an extremely poor quality study (if it can be called that as I believe it was just a poster for a conference).
I agree. To call it a 'study' is stretching the meaning of that word to the snapping point.

And not to be a total snot, but it was so poorly written what even if they'd established the minimal requirements for something approaching genuine research, it would have been hard to take seriously. This isn't a grammar Nazi quibble, but rather an observation that if the researchers are diligent and professional enough to mount a genuine, reproducible study, you kinda expect them to write it and present it in a professional way.

Was it really just a poster for a conference?

Now that I can believe.

On the other hand, it's a rather safe drug, so maybe worth a trial
I tend to be very cautious about throwing off-label-use drugs at ME, but so long as any potential experimenter looks at the side effects, both immediate and long-term, and possible interactions, there are worse things than spironolactone ...
 

Hip

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This is an extremely poor quality study (if it can be called that as I believe it was just a poster for a conference).

There's no control group, no blinding, subjective outcome criteria and it doesn't even specify what diagnostic criteria were used. It also doesn't specify how 'remission' was defined.
Indeed it is. But not really much in worse than many early phase studies, which often use no control group.

The first rituximab ME/CFS study comes to mind: just 3 people, no controls, and anecdotal outcome criteria. Given that all the early phase rituximab studies were positive, but the final large-scale phase III study came out negative, we should bear in mind that all early studies must be taken with a pinch of salt.

But it is interesting that there are some old threads on Phoenix Rising where people where reporting benefits from spironolactone, see:
In these threads, some reported that benefits from spironolactone manifested quickly, within weeks.



There is also a 2014 study on the benefits of spironolactone for fibromyalgia, where around 50% of patients found benefit, especially pain relief:

Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series
CONCLUSION
Fifteen of 31 women with otherwise treatment-resistant FMS experienced a number of prolonged beneficial effects from spironolactone on their complex pain-condition.

IMPLICATIONS AND DISCUSSION
We hypothesise that spironolactone affects several central and peripheral neurotransmitter systems such as γ-aminobutyric acid (GABA) activity and dopaminergic transmission.

The high rate of non-responsive patients underlines that FMS may represent several subgroups.

Pain relief and improvement of associated FHS-symptoms and positive effects on additional diseases or dysfunctions give reasons for marked and sustained improvement in the quality of life.

Well-controlled, double-blind, and randomised trials are necessary to confirm our potentially very important observations.



It lowers blood volume? You think that would be bad for every single ME patient, weird it helped some. But then again all these treatments appear to be different.
It's worth noting that in this ME/CFS spironolactone study, they initially gave spironolactone to 21 patients, but they found 5 of them had "intolerance" to this drug, so they dropped out right away, and the study was then conducted on the remaining 16 people.

I wonder whether it might be ME/CFS patients with POTS who dropped out, because some POTS patients have low blood volume and low aldosterone to begin with, so perhaps spironolactone was making the POTS worse.

This paper says:
Inappropriate low aldosterone and low blood volume have been identified in some patients with postural orthostatic tachycardia syndrome, so drospirenone-containing oral contraceptives are not recommended for use in this population
Drospirenone is a more potent spironolactone analogue.

That said, I have POTS (not sure if I have low blood volume though), and some years ago I tried spironolactone 25 mg daily for one week (for different purposes), and found this drug to be very well tolerated; although I did not notice any benefits, at least not during my short 1 week trial.



added to my to try list even thou I most likely don't have EBV. This drug is very cheap 2$ for month worth of supply in local pharmacy, how long do you think it takes for it to start working?
In the three Phoenix Rising threads linked to just above, some people were reporting benefits appearing after a few weeks. So as a guess, I would say a month or two might be required for the full benefits to manifest.
 
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Hip

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Note that spironolactone, as well as being potently anti-inflammatory, is also immunomodulatory, and conceivably this might help with viral clearance.

In particular, spironolactone should decrease Th17 immune cells; these Th17 cells have been linked to promoting EBV infection as well as promoting coxsackievirus B infection.

Spironolactone should reduce Th17 by reducing aldosterone, because aldosterone promotes Th17.

The Th17 immune response is useful for fighting Staphylococcus and Candida, but Th17 has a negative side as it appears to promote certain infections: high Th17 is linked to viral persistence, and causes a worsening of acute coxsackievirus B myocarditis. Elevated Th17 is also linked to making EBV mononucleosis worse.

This paper says:
In many viral infections, it appears that Th17 cells promote viral replication by inhibiting Th1 immune responses
 
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nerd

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This reminds me very much of Ivermectin. There are many similarities in vitro. It's anti-inflammatory, immunomodulatory, inhibits NF-kappaB and other viral-mediated proteins. Both are theoretically antiviral as well (including EBV). However, for both, it might be difficult to achieve sufficient concentration. For COVID-19, Ivermectin works because it achieves unequivocally high concentrations in lung tissue, and this is where SARS-CoV-2 pathology happens for the most part. But it's unclear if it reaches into the lymphatic system with notable concentrations.

You don't need an IC50, by the way. This kind of thinking derives from pathogens that replicate very quickly without any immune participation. But EC50 and IC50 should be quantified methodically differently because you need to consider other factors for complex chronic infections in vivo.

Th17 and the other immunological dysfunctions are just consequences down the line.

Nevertheless, you don't even need antivirals once you have antibodies and you have antibodies against acute EBV after your initial infection. What you miss is a proper immunological mechanism for latent and lytic infection. Antivirals don't help against these. They don't fix transfected lymphocytes and cleanse them from latent and lytic EBV activity. This is impossible. You can either get rid of transfected lymphocytes by identifying and filtering of transfected lymphocytes, which is only possible in the blood and not in the lymphatic system. Or you can try to suppress the latent and lytic signaling of EBV, which is a complex task because many of EBV's signaling pathways overlap with physiological function.

By the way, Ivermectin works exactly this way. It also suppresses viral signaling, not just cell invasion. But then again, it's unclear what concentrations you'd really need in the blood and in the lymphatic system and how it translates to oral doses. And when you reach the effective dose, it's also unclear how transfected cells really behave because there are still some signaling pathways left untouched. I assume that this kind of treatment will take a lot of time because the lymph system needs time until the lymphocyte profile is back to a normal level and functional in the response to transfected cells. It might take even longer, for example, to get rid of double-positive cells.

But this is a different topic. I don't understand why typical immunological treatments aren't regularly used with CFS/ME. They are used with almost any other autoimmune condition with the same lymphocyte profile. But they aren't with idiopathic autoimmune conditions, although the treatment doesn't target serology but immunology. It's nonsensical. Antibodies aren't the cause of any condition. They are a consequence. Treating the consequence has a greater potential, relatively speaking to the technology potential, so it shouldn't matter if you're seropositive or not.
 

Hip

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Th17 and the other immunological dysfunctions are just consequences down the line.
High Th17 may not necessarily be a dysfunction, it may be the result of the body fighting another infection. Both Staphylococcus and Candida trigger a strong Th17 response. High Th17 then suppresses Th1, and Th1 is used to fight the intracellular infections typically found in ME/CFS.

Similarly with Th2: this is triggered by extracellular bacterial infection, and once triggered will tend to suppress Th1.



What you miss is a proper immunological mechanism for latent and lytic infection. Antivirals don't help against these.
In addition to latent and lytic infections, it is possible that ME/CFS might involve abortive infections.

Abortive infections occur when a virus enters a cell which does not possess the necessary internal environment to facilitate the full viral life cycle, so the life cycle gets aborted before new virions are created and can escape the cell; but the virus nevertheless is constantly trying to replicate within the cell, so it is an ongoing infection.

There are some theories that ME/CFS may be caused by abortive herpesvirus infections.
 

nerd

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High Th17 may not necessarily be a dysfunction, it may be the result of the body fighting another infection.
True. I mean chronically elevated levels. The body isn't designed/evolved to fight chronic infections.

Abortive infections occur when a virus enters a cell which does not possess the necessary internal environment to facilitate the full viral life cycle, so the life cycle gets aborted before new virions are created and can escape the cell; but the virus nevertheless is constantly trying to replicate within the cell, so it is an ongoing infection.
This is what I typically call transfected cells. Some also called it residual viral activity.
 
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High Th17 may not necessarily be a dysfunction, it may be the result of the body fighting another infection. Both Staphylococcus and Candida trigger a strong Th17 response. High Th17 then suppresses Th1, and Th1 is used to fight the intracellular infections typically found in ME/CFS.

Similarly with Th2: this is triggered by extracellular bacterial infection, and once triggered will tend to suppress Th1.





In addition to latent and lytic infections, it is possible that ME/CFS might involve abortive infections.

Abortive infections occur when a virus enters a cell which does not possess the necessary internal environment to facilitate the full viral life cycle, so the life cycle gets aborted before new virions are created and can escape the cell; but the virus nevertheless is constantly trying to replicate within the cell, so it is an ongoing infection.

There are some theories that ME/CFS may be caused by abortive herpesvirus infections.
Hello Hip. Are you familiar with Anthony William (MM) ?